In the past decade a number of studies have illuminated the characteristics and functional role of the rodent and human TRPV1 receptor.  This receptor, which is widespread in many tissues of the body, seems to be principally involved in mediating nociceptive responses to heat, low pH and vanilloid agonists such as capsaicin and resiniferatoxin.  The possibility that endogenous vanilloids resulting from tissue injury or inflammation may be acting via stimulation of TRPV1 has led to the pursuit of a variety of chemical structures that possess TRPV1 antagonist properties.  Such compounds may have usefulness as analgesic agents in the treatment of certain types of pain.

            Our lab has designed several series of compounds (Template I) intended to meet the requirements of the TRPV1 antagonist pharmacophore.  Previous studies of vanilloid agonists have identified the importance of an aromatic A region, a polar B region, and a hydrophobic C region.  In addition, our compounds have included a heteroatom (X = alcohol or amido) intended to interact with a proposed D region.  Antagonist properties were expected to be conferred by a suitable mismatch between drug and receptor in one of these regions.

            The synthesis of these compounds and the results of preliminary biological testing will be presented.